Cooperation between a coenzyme A-independent stand-alone initiation module and an iterative type I polyketide synthase during synthesis of mycobacterial phenolic glycolipids.
Cooperation between a coenzyme A-independent stand-alone initiation module and an iterative type I polyketide synthase during synthesis of mycobacterial phenolic glycolipids.
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DOI：
10.1021/ja904792q
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发表时间：
2009-11-25
影响因子：
15
通讯作者：
Quadri, Luis E. N.
中科院分区：
文献类型：
--
作者：
He, Weiguo;Soll, Clifford E.;Chavadi, Sivagami Sundaram;Zhang, Guangtao;Warren, J. David;Quadri, Luis E. N.
几种结核分枝杆菌菌株、麻风分枝杆菌和其他分枝杆菌病原体产生一组称为酚糖脂（PGLs）的小分子毒力因子。PGLs在致病性和宿主-病原体相互作用中起关键作用。因此，PGL生物合成途径的阐明不仅将扩大我们对天然产物生物合成的理解，而且还可能阐明新疗法的途径，以提供针对分枝杆菌感染的替代防线。在这项研究中，我们报告的PGL生物合成的长链对羟基苯烷酸中间体的生产的酶的要求的调查。我们证明了一个辅酶A独立的双结构域起始模块（FadD 22）和一个6-域减少迭代I型聚酮合酶（Pks 15/1）之间的功能合作，用于在体外和体内FadD 22-Pks 15/1重建系统中生产对羟基苯基链烷酸酯中间体。我们的研究结果表明，Pks 15/1是一个迭代的I型聚酮合酶的催化循环迭代，一个机械属性，解释了在分枝杆菌PGLs中看到的特征性烷基链长度变异的起源一个宽松的控制。FadD 22-Pks 15/1重组系统为进一步揭示Pks 15/1最终产物结构的迭代催化控制机制以及研究FadD 22-Pks 15/1系统与PGL生物合成途径下游酶的功能伙伴关系奠定了初步基础。
Several Mycobacterium tuberculosis strains, Mycobacterium leprae, and other mycobacterial pathogens produce a group of small-molecule virulence factors called phenolic glycolipids (PGLs). PGLs play key roles in pathogenicity and host−pathogen interaction. Thus, elucidation of the PGL biosynthetic pathway will not only expand our understanding of natural product biosynthesis, but may also illuminate routes to novel therapeutics to afford alternative lines of defense against mycobacterial infections. In this study, we report an investigation of the enzymatic requirements for the production of long-chain p-hydroxyphenylalkanoate intermediates of PGL biosynthesis. We demonstrate a functional cooperation between a coenzyme A-independent stand-alone didomain initiation module (FadD22) and a 6-domain reducing iterative type I polyketide synthase (Pks15/1) for production of p-hydroxyphenylalkanoate intermediates in in vitro and in vivo FadD22-Pks15/1 reconstituted systems. Our results suggest that Pks15/1 is an iterative type I polyketide synthase with a relaxed control of catalytic cycle iterations, a mechanistic property that explains the origin of a characteristic alkyl chain length variability seen in mycobacterial PGLs. The FadD22-Pks15/1 reconstituted systems lay an initial foundation for future efforts to unveil the mechanism of iterative catalysis control by which the structures of the final products of Pks15/1 are defined, and to scrutinize the functional partnerships of the FadD22-Pks15/1 system with downstream enzymes of the PGL biosynthetic pathway.
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影响因子：
2.9
作者：
Quadri, LEN;Weinreb, PH;Walsh, CT
通讯作者：
Walsh, CT
影响因子：
2.9
作者：
Quadri, LEN;Keating, TA;Walsh, CT
通讯作者：
Walsh, CT
影响因子：
6.4
作者：
Tsenova, L;Ellison, E;Kaplan, G
通讯作者：
Kaplan, G
影响因子：
4.6
作者：
AuBuchon, J. P.;de Wildt-Eggen, J.;Dumont, L. J.
通讯作者：
Dumont, L. J.
影响因子：
--
作者：
Quadri, Luis E. N.
通讯作者：
Quadri, Luis E. N.